Economic burden related to fistulas or strictures among commercially insured patients with Crohn’s disease in the United States

BACKGROUND: Crohn’s disease (CD) is a chronic, progressive, immune-mediated gastrointestinal condition that can lead to fistulizing or stricturing complications. OBJECTIVE: To quantify the burden of illness related to fistulas and/or strictures in patients with CD. METHODS: Using the Optum Research Database from October 2015 to December 2019, patients with CD were classified according to 1 of 3 condition cohorts: CD with fistula (CD-F), CD with stricture (CD-S), or CD with fistula and stricture (CD-FS). Each cohort was matched to a nonfistula, nonstricture CD cohort. Postdiagnosis per patient per year (PPPY) costs and health care resource utilization were assessed, accounting for variable lengths of follow-up periods. Multivariable generalized linear models were used to estimate the adjusted mean costs in each cohort. RESULTS: The CD-F, CD-S, and CD-FS cohorts included 1,317; 4,650; and 894 patients, respectively. The mean age of patients within the CD-S and their comparator cohorts was higher than in the CD-F or CD-FS cohorts (59.9 vs 49.5 vs 49.6 years). At baseline, cardiovascular disease was the most common comorbidity across all condition and comparator cohorts. Condition cohorts had 2-4 times more inpatient visits, 5-8 times more surgical visits, and 2-3 times more endoscopies PPPY than comparator cohorts. Compared with their respective comparator cohort, patients in the 3 condition cohorts had higher medication, medical, and total health care costs. CONCLUSIONS: This study demonstrates a significant economic burden related to fistulas and/or strictures among patients with CD, highlighting the importance of prevention, early recognition, and appropriate management of CD-related complications.


Plain language summary
Patients with Crohn's disease may experience complications in the gut. These include fistulae, which are abnormal connections between the gut or other organs, and strictures, which are areas of abnormal narrowing. Limited data are available on the burden of illness in patients with these complications. We analyzed data from a United States-based database of patients with Crohn's disease. We found that Crohn's disease complications are linked with higher disease burden and costs compared with patients without these complications.

Implications for managed care pharmacy
This study shows that patients with Crohn's disease and complications of fistula and/or stricture incur higher medication/medical costs and experience more surgical and/or inpatient/outpatient visits than patients with Crohn's disease without these complications. The significant economic burden of Crohn's disease-related complications highlighted herein may help to inform health care practitioners and policymakers on the importance of prevention, early recognition, and the appropriate management of these complications.
Crohn's disease (CD) is a chronic, progressive inflammatory disease of the gastrointestinal tract, often characterized by alternating episodes of recurrent flares and clinical remission. [1][2][3] Chronic inflammation associated with CD can lead to bowel damage and the development of intestinal complications including fistulas and/or strictures that lead to reduced intestinal function. Furthermore, CD is associated with various comorbidities, such as cardiovascular disease, hepatic disease, metabolic disease, and psychiatric disorders. 3,4 Although most patients present with an inflammatory phenotype at diagnosis, up to half of adult patients with CD develop fistulas or strictures within 20 years after diagnosis. 5,6 CD management strategies in therapeutic trials and clinical practice aim to induce and maintain clinical and endoscopic remission, with the goal of preventing complications and progressive bowel damage. Several biologic agents across multiple classes are approved for the treatment of inflammatory CD. 7 However, the mainstay of treatment for complicated CD (which can include complications such as strictures and/or fistulas) remains surgical; to date, there are no approved pharmacologic treatments for stricturing disease, and only 2 therapies are approved for fistulizing disease. 8 Overall, 40%-71% of patients require surgical treatment for complications within 10 years after diagnosis. 9 Despite the disease burden of fistulizing and/or stricturing disease on individual patients with CD, real-world evidence characterizing this patient population, as well as the economic burden associated with these complications, is scarce. Limited evidence shows that CD is associated with increased health care costs. 3,10-13 On average, a patient with CD incurs $8,023 per year in incremental direct and indirect costs, corresponding to an overall cost of approximately $3.48 billion in the United States per annum, which is projected to increase to $3.72 billion by 2025. 12 This study examined the clinical characteristics, allcause health care resource utilization (HCRU), direct costs, and economic burden of patients with CD and fistulas (CD-F), CD and stricture (CD-S), and CD with fistulas and strictures (CD-FS), each matched to a corresponding cohort of patients with uncomplicated CD (defined as those without strictures or fistulas).

STUDY DESIGN
This retrospective cohort study aimed to review claims data from the Optum Research Database, a US administrative claims database, from October 2015 to December 2019. The Optum Research Database contains longitudinal medical and pharmacy administrative claims from commercial plans across the United States. Three incident condition cohorts (CD-F, CD-S, and CD-FS) were evaluated. Each condition cohort was separately matched 1:1 by age (±3 years), sex, insurance type, and region of residence to a comparator cohort of patients with CD but without fistulas or strictures.
All patients included in the analyses were aged 18 years or older at the index date and had at least 1 inpatient or 2 outpatient claims, with a diagnosis of CD (International Classification of Diseases, Ninth and Tenth Revisions) diagnosis codes prior to the index date.
The index date was the date of first diagnosis with fistula and/or stricture for the condition cohorts. For the comparator cohorts, the index date was the date of an inpatient or outpatient claim (including emergency department [ED] claim) with a CD diagnosis code within 30 days and the closest to the index date of the fistula, stricture, or fistula and stricture patient. The baseline period was 12 months before the index date (inclusive of the index date). For the CD-F or CD-S cohorts, follow-up time was from the index date and continued to either the last date of enrollment, the end of the study period, or the occurrence of a second condition of interest (fistula or stricture), whichever occurred first. For the CD-FS cohort, follow-up time started from the date of the claim with the diagnosis code of the second condition of fistula or stricture and continued to either the last date of enrollment or the end of the study period, whichever occurred first. Patients without fistula or stricture were followed from their index date until the end of continuous enrollment or the end of the study, whichever occurred first.
An overall schematic of the study design is presented in Supplementary Figure 1, available in the online article.

STUDY OUTCOMES
The study outcomes include the demographic and clinical characteristics of patients with CD and fistula and/or stricture vs patients with CD and no fistula or stricture (as comparator cohorts) and the clinical (comorbidities and medications) and economic (direct health care cost and HCRU) burden of disease among these patient groups. Demographic characteristics and the baseline prevalence of comorbidities were compared between each condition cohort and their respective comparator cohort. Patients were considered as having comorbidities if they had at least 1 medical claim with diagnosis codes for the relevant condition. Prevalence was measured as the proportion of patients with a comorbidity. It was calculated as the number of patients with the comorbidity of interest divided by the capitated insurance plans were excluded from the HCRU and total costs analyses because the actual costs were not provided in the data source.

STATISTICAL ANALYSES
Descriptive analyses were conducted to assess demographics, comorbidities, direct costs, and HCRU at baseline and follow-up. Mean and SD were reported for continuous variables; frequency and percentages were reported for categorical variables. In addition, median and interquartile values were reported for cost variables because of their skewed distribution. Multivariable generalized linear models with Poisson distribution were used to compare the total number of patients in the cohort and then compared between each condition cohort and its respective comparator cohort.
HCRU was assessed in each of the condition cohorts and their respective comparator cohorts at baseline and during follow-up; this included the type of visit (outpatient/inpatient/ED), length of hospital stay, relevant specialty of the treating physician, CD-related procedures and surgeries, and medications dispensed. The medical costs (outpatient visits, inpatients visits [hospitalizations], and ED visits), pharmacy costs, and total costs (medical and pharmacy costs) were calculated per patient per year (PPPY) for each cohort in the baseline and follow-up periods. Patients with     Most patients in the CD-S and CD-FS condition and comparator cohorts were female. Furthermore, most patients in the CD-F and CD-FS condition and comparator cohorts number of outpatient, inpatient, or ED visits PPPY between condition and comparator cohorts in the follow-up period.

DEMOGRAPHICS AND CLINICAL CHARACTERISTICS
To estimate the adjusted mean costs for each cohort, a propensity score overlap weighting (PSOW) model for developing CD complications was used. The PSOW model is a PS balancing method, which is an efficient method to control for imbalances in baseline characteristics between cohorts and achieve an exact match between condition and comparator cohorts to estimate the adjusted mean costs for each cohort. The PSOW method is different from the inverse probability of treatment weights method, in which outlier values are not accounted for. It is used in conjunction with generalized linear models with gamma distribution and log link function in our study. In the PSOW model, variables were used as predictors, which included patient demographics, baseline comorbidities, baseline cost, and cohort assignment. The weight was calculated as follows: for each patient, if case equals 1, then weight was 1 minus PS; if case equals 0 (comparator), then the weight equals PS. The outcomes in the PSOW model included the direct costs: medical cost, pharmacy cost, and total costs (medical and pharmacy costs).
Bootstrapping methodology was used to calculate 95% CIs of adjusted mean costs and the predicted difference

ALL-CAUSE HCRU IN THE FOLLOW-UP PERIOD
Over the follow-up period, the number of inpatient admissions, outpatient visits, gastroenterology visits, radiology held a commercial health plan, the most common of which was a point-of-service plan (Table 1).

Baseline Clinical Characteristics and Comorbidities.
The prevalence of comorbidities was numerically lower in patients with CD-F and CD-S than in their comparator cohorts; conversely, there was a higher prevalence of comorbidities in patients with CD-FS than in their comparator cohort (Supplementary Figure 2 and Supplementary  Table 2). Across all condition and comparator cohorts, cardiovascular disease was the most common comorbidity, followed closely by hypertension (Supplementary Figure 2  and Supplementary Table 2). The distribution of disease location at baseline varied between patients with CD-F, CD-S, CD-FS, and their comparator cohorts (Table 2). Patients with CD-F and

UNADJUSTED ALL-CAUSE HEALTH CARE COSTS PPPY IN THE FOLLOW-UP PERIOD
During follow-up, the costs associated with CD-related procedures or CD-related surgeries, medication, and outpatient visits PPPY were significantly higher for all condition cohorts compared with those of their respective comparator cohorts (Table 4). Patients with CD-S had a higher total health care cost (mean difference=$84,357 PPPY; P < 0.0001) and higher total medical costs than patients in their comparator cohort visits, and surgery specialty visits PPPY was significantly higher for all condition cohorts compared with those in the respective comparator cohorts (P < 0.0001 for all comparisons) ( Table 3). Across all condition cohorts, all procedures (ie, the number of abscess drainages, endoscopies, computer tomography of the abdomen/pelvis, and colectomy) were significantly higher in HCRU PPPY compared with their respective comparator cohorts (P < 0.0001 for all comparisons; Table 3).  comparator cohorts. The adjusted differences in medication, medical, and total costs PPPY were $9,864, $57,746, and $65,017, respectively, for patients with CD-F vs their comparators; $4,936, $77,534, and $81,598, respectively, for those with CD-S vs comparators; and $14,900, $67,811, and $83,538, respectively, for those with CD-FS vs comparators ( Figure 1).

Discussion
Overall, our study has several important findings. In patients with complicated CD, all-cause HCRU (PPPY), including inpatient and outpatient encounters, ED visits, and gastroenterology, radiology, and surgery specialty visits, was higher than that for those without complications.
Adjusted Incremental Cost PPPY. Four patients with an extremely high follow-up cost (>$10 million) were excluded from the multivariable analyses. After adjusting for baseline imbalances between condition and comparator cohorts, patients with CD-F, CD-S, and CD-FS still had significantly higher medication, medical, and total costs than their enable an overall population-based reduction in HCRU. 20-22

LIMITATIONS
Several limitations related to this study need to be acknowledged. As data were derived from a commercially insured population, including Medicare Advantage patients who have a separate drug formulary list compared with commercially insured patients (and thus limited coverage for treatments), the analyzed patients may not be generalizable to all patients with CD in the United States. Furthermore, cohorts and comorbidities are defined by diagnosis codes, so these may be limited by inaccuracy or misclassification of coding in the claims data. Finally, despite the adoption of matching and the use of the PSOW method, some relevant variables are unmeasured or unmeasurable in claims data and cannot be included to further balance the condition and comparator cohorts. Therefore, there is a possibility of residual confounding that may lead to an overestimated or underestimated burden of complicated CD.

Conclusions
The disease burden and costs associated with fistulizing or stricturing CD are significantly greater than what is observed for patients without these complications, highlighting the high care burden incurred by complications from CD. Moreover, the large proportion of patients with health care encounters in the condition cohorts suggests that patients require more medical management for their complications. Although there are limited data available from previous studies to place these findings into context, this study shows the importance of preventing and lowering the risk of CD complications, developing targeted pharmacologic interventions to effectively treat complicated CD, and ensuring appropriate and timely care and management of patients with CD. Similarly, the all-cause HCRU (PPPY), including both medication and medical costs, was higher in patients with complicated CD than in those without CD complications. Finally, we demonstrated that incremental medication, medical, and total health care costs (PPPY) associated with fistula or/and stricture were significant.

DISCLOSURES
In line with what has been previously reported, high costs were associated with the care of complicated CD. Previous studies have shown that costs were driven by hospitalization, surgery, outpatient visits, or medication costs [13][14][15] ; however, in this study, hospitalizations and CD-related procedures are identified as 2 key cost drivers.
Although the cumulative risk of developing fistulizing or stricturing disease is reported to be 50.8% at 20 years after diagnosis, 6 early pharmacologic intervention is a potential strategy in preventing future disease progression. [16][17][18][19] The REACT study, an open-label cluster randomized controlled trial of early combined immunosuppression vs conventional management in community gastroenterology practices from Belgium and Canada, showed that early combined immunosuppression was associated with a reduction in surgery, hospital admissions, and serious disease-related complications in patients with CD, suggesting that the disease course can be altered to prevent the development of complications. 17 In recent years, there has been an increased use of innovative and targeted pharmacologic treatments for CD. Although their prescribed use may also drive treatment costs, in the long term, when averaged over the disease population, better and earlier control of disease to prevent progression could lead to a reduction in invasive procedures and hospitalizations (the 2 key cost drivers identified in this study) and thus potentially